Hydrophilic, lubricious medical devices having contrast for magnetic resonance imaging

ABSTRACT

Disclosed are medical devices having lubricious coatings which are capable of producing magnetic resonance image in the presence of a suitable magnetic field. The medical devices are easy to manipulate in body channels because of reduced friction with tissue surfaces and can be readily visualized in real time, which greatly facilitates the tracking of the medical devices while present within the bodies of humans or animals. The level of magnetic susceptible agent in the coatings of medical devices can be easily controlled by the present invention to give the desired performance. Coating processes to produce these medical devices are also disclosed.

This application claims the benefit of provisional application No.60/231,601, filed Sep. 11, 2000.

FIELD OF THE INVENTION

The present invention relates to hydrophilic lubricious coatings formedical devices that can be detected by magnetic resonance imaging.

BACKGROUND OF THE INVENTION

A variety of lubricious coatings have been proposed for use on thesurfaces of medical devices such as, for example, catheters, guidewires, endotracheal tubes and implants. Common materials used in the artto provide lubricious coatings for medical devices include, for example,oil, silicone, and polymeric materials, such aspoly(N-vinylpyrrolidone), hydrophilic polyurethanes, Teflon,poly(ethylene oxide) and poly(acrylic acid). Among the most commonmaterials used to provide lubricious coatings are hydrophilic polymerswhich are covalently bonded to the substrate with a binder polymerhaving reactive functional groups, e.g., isocyanate, aldehyde, and epoxygroups. Other binder polymers comprise, for example, copolymerscontaining a vinyl moiety. Details of such coatings are disclosed, forexample, in U.S. Pat. Nos. 5,091,205 issued Feb. 25, 1992 and 5,731,087issued Mar. 24, 1998.

Medical device coatings that are visible in magnetic resonance imaging(MRI) provide the opportunity to use magnetic resonance to performtherapeutic procedures. The possible uses of image guided therapyotherwise known as interventional MR are extensive. Examples of theseapplications include monitoring ultrasound and laser ablations, guidingthe placement of biopsy needles, endovascular therapy, and visualizingdisease, such as tumors, inter-operatively. This type of interventionaltherapy eliminates the hazards of ionizing radiation associated withx-ray fluoroscopy. At the same time, it acquires real-time images inthree dimensions and due to the sensitivity of the MR to the test tissueenvironmental it can also provide additional diagnostic information. Asused herein, the term “real-time” means that the visualization of themedical device is synchronized with the movement of the device in thebody of the patient.

MRI shares the same underlying theory as nuclear magnetic resonance(NMR). Contrast is obtained when water protons in of the test tissuehave shorter relaxation times relative to the protons of other watermolecules in the environment around the tissue. Contrast can be enhancedby the presence of an agent that can shorten the relaxation time ofwater protons even further. Such agents operate in the following manner.When protons are pulsed with a radio-frequency pulse in a magneticfield, their nuclear dipoles are a certain angle out of phase with theapplied magnetic field. Longitudinal relaxation is the drift back of theprotons back to their original alignment with the magnetic field.Paramagnetic contrast agents facilitate this relaxation process byaccommodating the excess energy from the protons caused by the pulsing.Gadolinium has become the paramagnetic ion most often used in the artbecause it has the largest number of unpaired electrons in the 4forbitals and therefore exhibits the greatest longitudinal (T₁)relaxivity of any element. In the presence of gadolinium, some of themagnetic energy of the nuclei in the high-energy state can transferenergy to gadolinium and the gadolinium can accept this energy becauseof its magnetic susceptibility.

Alternatively, contrast in magnetic resonance is also commonly achievedusing super-paramagnetic particles. Typically, iron oxide nanoparticlesare used because can they enhance the rate of the spin-spin or T₂(transverse) relaxation. This is accomplished in the following way.After a 90° radio-frequency pulse in the x direction, a magnetizationcomponent appears in the y direction. This can be pictured as thenuclear dipoles bunched together and precessing around the surface of adouble cone transverse to the applied magnetic field. This condition iscalled phase coherence. Super-paramagnetic particles causeinhomogeneities in the applied magnetic field resulting in differenteffective magnetic fields for each of the nuclei. These inhomogeneitiescause the nuclei to lose phase coherence at a faster rate relative toproton nuclei that are not in the presence of super-paramagneticparticles.

In order to detect medical devices in using MRI, gadolinium complexeshave been grafted onto the surface of polymer substrates. For example,in PCT patent application publication number WO 99/60920, there isdisclosed a magnetic resonance (MR) signal-emitting coating whichincludes a paramagnetic metal ion-containing polymer complex and amethod of visualizing medical devices in magnetic resonance imaging,which includes the step of coating the devices with the paramagnetic-ioncontaining polymer. The patent application further discloses a coatingfor visualizing medical devices in magnetic resonance imaging,comprising a complex of formula (I):P-X-L-M^(n+)  (I)Wherein P is a polymer, X is a surface functional group, L is a chelate,M is a paramagnetic ion and n is an integer that is 2 or greater.Benefits may be realized from the approach disclosed in the patentapplication over the “active visualization” technique method since iteliminates the need for the incorporation of RF coils and transmittingwires into the device and it provides visualization of the completedevice and not merely the tip. However, this approach appears to becomplex because of the necessity to engage in chemical grafting andplasma treatment. Further, it is believed to be extremely difficult toimplement for a commercial-scale application.

Consequently, a simple coating process that is compatible with currenthydrophilic, lubricious coating technology to impart such MRI capabilityto a medical device is desired in the art.

SUMMARY OF THE INVENTION

In accordance with the present invention, improved lubricious medicaldevices such as, for example, catheters, guide wires, endotrachealtubes, balloons and implants are provided. The medical devices of thepresent invention comprise a hydrophilic, lubricous coating and an agentwhich is magnetic susceptible. The agent is physically incorporated intothe lubricious coating, or migrates from a polymeric matrix into thelubricious coating upon hydration.

By the present invention it is now possible to prepare devices that areboth lubricious and visible in MR using easily controlled and simplemanufacturing processes.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a comparison of spectra from an elemental analysis of ascanning electron microscope of an uncoated specimen and a coatedspecimen.

FIG. 2 shows a cross-section of a 7 french guide wire composed of anylon-polyethylene copolymer with imbibed gadolinium salt.

FIG. 3 shows a cross-section of a nylon-polyethylene copolymer substratecoated with a gadolinium complex and overcoated with cellulose acetate.

DESCRIPTION OF THE INVENTION

The magnetic susceptible agents useful in accordance with the presentinvention can be any materials, elements or ions that have magneticsusceptibility, e.g., can produce a contrast in magnetic resonanceimaging. Typical ingredients suitable for use in accordance with thepresent invention include, for example, paramagnetic ions, paramagneticion complexes and super-paramagnetic particles. A preferred magneticsusceptible agent is diethylenetriamine-pentaacetic acid gadolinium(III) dihydrogen salt. Other preferred magnetic susceptible agentsinclude organometallic complexes, such as, but not limited to,tetrazazcyclotetradecane tetraacetic acid gadolinium complex andtetrazazcyclododecane tetraacetic acid gadolinium complex. Otherpreferred multivalent paramagnetic metals include, for example, iron,manganese, chromium, cobalt, and nickel. An especially preferredparamagnetic ion is gadolinium. Other suitable magnetic susceptibleagents are disclosed, for example, by Jinkins J. R., America J. ofNeuroradiology, 1992, 13, 19-27. Further details concerning theselection of suitable magnetic susceptible agents are known to thoseskilled in the art.

The lubricious polymers suitable for use in accordance with the presentinvention comprise any polymers which are substantially more lubricouswhen wetted with an aqueous liquid than when dried, e.g., as evidencedby a reduction in the coefficient of friction. Typically, the lubriciouspolymers have a water solubility of at least about 1.0 wt % andpreferably at least about 2.0 wt. % or are water-swellable. As usedherein, the term “water-swellable” means a substantially hydrophilicpolymer which, even though is not soluble in water, would absorbsufficient water to render it lubricious in the hydrated state. Inaddition, the term “hydrophilic” as used herein means that waterdroplets do not readily form beads on the surface of such hydrophilicmaterial, but instead the water droplets tend to assume a contact angleof less than 45° and readily spread on its surface. Further detailsconcerning hydrophilic coatings which are useful for purposes of thisinvention are disclosed by Fan, Y. L. “Hydrophilic Lubricity in MedicalApplications”, Encyclopedia Handbook of Biomaterials and Bioengineering,edited by D. L. Wide, Part A, Vol. 2, p 1331.

Preferred hydrophilic polymers include, but are not limited to, thoseselected from the group consisting of polyvinyl compounds,polysaccharides, polyurethanes, polyacrylates, polyacrylamides,polyalkylene oxides, and copolymers, complexes, mixtures, andderivatives thereof. Poly(N-vinyl lactams) are preferred polyvinylcompounds for use in accordance with the present invention. The term“poly(N-vinyl lactam)” as used herein means homopolymers and copolymersof such N-vinyl lactams as N-vinyl pyrrolidone, N-vinyl butyrolactam,N-vinyl caprolactam, and the like, as well as the foregoing preparedwith minor amounts, for example, up to about 20 weight percent, of oneor a mixture of other vinyl monomers copolymerizable with the N-vinyllactams. Of the poly(N-vinyl lactams), the poly(N-vinyl pyrrolidone)homopolymers are preferred. A variety of poly(N-vinyl pyrrolidones) arecommercially available and of these a poly(N-vinyl pyrrolidone) having aK-value of at least about 30 is especially preferred. The K value is ameasure of molecular weight, the details of which are known to thoseskilled in the art. Other preferred hydrophilic polymers for use inaccordance with the present invention include, but are not limited to,those selected from the group consisting ofN-vinylpyrrolidone-hydroxyethyl acrylate copolymers, carboxymethylcellulose, hydroxyethyl cellulose, polyacrylamide,poly(hydroxyethyl-acrylate), cationically-modified hydroxyethylcellulose, poly(acrylic acid), poly(ethylene oxides), and complexes,mixtures, and derivatives thereof. Especially preferred arepoly(N-vinylpyrrolidone), poly(acrylic acid), poly(ethylene oxide) andcellulosics, such as, for example, carboxymethyl cellulose andcationically modified cellulose.

The lubricious polymers suitable for use in accordance with the presentinvention can be nonionic, cationic, anionic or amphoteric. Typically,the molecular weight of the lubricious polymers is from about 100,000 to2,000,000,000 grams per gram mole, preferably from about 200,000 to5,000,000 grams per gram mole, and, more preferably, from about 300,000to 2,000,000 grams per gram mole. As used herein, the term “molecularweight” means weight average molecular weight. Methods for determiningweight average molecular weight, e.g., light scattering, are known tothose skilled in the art. Further details concerning the preparation andselection of lubricious polymers suitable for use in accordance with thepresent invention are known to those skilled in the art. Such lubriciouspolymers are readily commercially available from a variety of sourcessuch as, for example, Union Carbide Corporation, Danbury, Conn.

Preferably, a binder polymer having functionality to promote bonding ofthe lubricious polymer to the medical device substrate is used inaccordance with the present invention. Typical binder polymers comprisemoieties which form a covalent bond between the binder polymer and thelubricious polymer, e.g., isocyanate, aldehyde or epoxy moieties, orthose which primarily form a hydrogen or ionic bond, e.g, polymers whichcomprise a vinyl moiety, such as vinyl chloride or vinyl acetate and acarboxylic acid moiety. Further details of such binder polymers areknown in the art and described for example in U.S. Pat. Nos. 5,091,205issued Feb. 25, 1992 and 5,731,087 issued Mar. 24, 1998.

In addition to the binder polymers and lubricious polymers and magneticsusceptible agents, the lubricious coatings of the present invention maycomprise one or more additives normally used in coating formulationssuch as, for example, surfactants, preservatives, viscosity modifiers,pigments, dyes, physiologically active agents and other additives knownto those skilled in the art. Typical physiologically active ingredientsinclude, for example, therapeutic agents, antithrombogenic agents,antimicrobial agents and antibiotic agents. When ionic additives areemployed in the coating, e.g., heparin, which is anionic, it ispreferred to use a cationic lubricious polymer, e.g., acationically-modified hydroxyethyl cellulose. Similarly, when anadditive is cationic, it is preferred to use an anionic lubriciouspolymer, e.g., a polyacrylic acid-acrylamide polymer. The combination ofan additive and a lubricious polymer may be varied as needed to providethe desired performance.

The substrates having surfaces upon which the lubricious coatings of thepresent invention can be applied are not limited. The substances whichare usable for the substrates include, but are not limited to, variousorganic polymeric compounds such as, for example, polyamides,polyesters, e.g., polyethylene terephthalate and polystyreneterephthalate, polyvinyl chloride, polyvinylidene chloride, polystyrene,polyacrylic esters, polymethylmethacrylate and other polymethacrylicesters, polyacrylonitrile, polyethylene, polypropylene, polyurethane,polyvinyl acetate, silicone resins, polycarbonate, polysulfone,polybutadiene-styrene copolymers, polyisoprene, nylon, polyethylene,polypropylene, polybutylene, halogenated polyolefins, various latexes,various copolymers, various derivatives and blends thereof. Thesubstrates may also comprise, in addition to the substrate polymer,various inorganic and metallic substances such as, for example, glass,ceramics, stainless steel, and a super elastic metal or shape memoryalloys such as Ni—Ti alloy, for example. Typical medical devices towhich the lubricious coatings of the present invention can be appliedinclude, but are not limited to, catheters, balloon catheters, guidewires, endotracheal tubes, implants and other medical devices.

The lubricious coatings of the present invention may be applied byeither a two-step coating process or a one-step coating process. In apreferred two-step coating process, the portion of the substrate to becoated is first coated with the binder polymer and subsequently coatedwith the lubricious polymer. In a preferred one-step coating process,the binder polymer and lubricious polymer are applied to the substratein a single step. Any conventional liquid coating processes may beutilized in accordance with the present invention. Such processesinclude, for example, dip-coating, spray-coating, knife-coating androller coating. Dip-coating is a preferred coating method in accordancewith the present invention.

In preferred coating processes of the present invention, the binderpolymers and the lubricious polymers may be delivered from liquidscontained in either a solution, a dispersion or an emulsion of thepolymers, e.g., the binder polymer being applied in a first liquidmedium and the lubricious polymer being applied in a second liquidmedium. In the one-step coating methods, the binder polymers and thelubricious polymers are contained in the same, i.e., common liquidmedium. In the two-step methods, the binder polymers and the lubriciouspolymers are contained in separate liquid mediums. Additional coatingsteps may also be employed to introduce different polymers or additives,e.g., the physiologically active ingredient as hereinafter described.The liquid mediums used for delivering the binder polymers andlubricious polymers may be organic, aqueous or an organic-aqueousmixture. The liquid medium used for delivering the binder polymer can beselected so that it has some solvency for the substrate, i.e., when thesubstrate is polymeric. This can enhance the adhesion between the binderpolymer and the substrate and aid to the film formation of the coatingmaterial. Preferred liquid mediums for delivering the binder polymersand lubricious polymers include, but are not limited to, esters, e.g.,ethyl acetate, isopropyl acetate, ethyl lactate; alcohols, e.g.,isopropyl alcohol, ethanol, butanol; ketones, e.g., acetone,methylethylketone, diacetone alcohol, methyl isobutyl ketone; amidessuch as dimethyl formamide; toluene; glycol ethers such as butyl glycolether; chlorinated solvents such as dichloroethane, water, and mixturesthereof. Preferably, the liquid mediums are selected so that the binderpolymers and lubricious polymer evenly wet the surface of the substrateto be coated. The additives, when employed, may be contained in eitheror both of the liquid mediums containing the binder polymer or thelubricious polymer or may be contained in a separate liquid medium.

In a preferred aspect of the present invention, an additional coatingcan be applied to inhibit the diffusion of the magnetic susceptibleagent out of the coating into body fluids. The additional coating istypically comprised of a coating agent, e.g., a polymer such ascellulose acetate, which is effective to inhibit the diffusion of themagnetic susceptible out of the hydrophilic coating. The selection,amount and application of the coating agent can be readily determined bythose skilled in the art.

Preferably, the concentration of the binder polymer and the lubriciouspolymers in the liquid mediums are sufficient to provide the desiredamounts of the respective polymers in the lubricious coatings.Typically, the concentration of the binder polymers in the liquid mediumwill range from about 0.05 to 10 weight percent and, preferably, fromabout 0.2 to 2 weight percent based on the total weight of the liquidmedium. Typically, the concentration of the lubricious polymers willrange from about 0.1 to 20 weight percent and, preferably, from about0.5 to 5 weight percent, based upon the total weight of the liquidmedium. Further details concerning the selection of liquid mediums fordelivering the binder polymers and lubricious polymers of the presentinvention are known to those skilled in the art. The concentration ofadditives in the liquid medium is dependent on the particular additiveand desired effect and can be determined by those skilled in the art.

The coating processes of the present invention are preferably conductedin a liquid phase at atmospheric pressure and at a temperature fromabout 20 to 90° C. The residence times for contacting the surface of thesubstrate to be coated with the liquid mediums containing the binderpolymer or the lubricious polymer, or both, range from about 1 second to30 minutes, preferably from about 5 seconds to 10 minutes. It isgenerally desirable to dry the coatings after application of the coatingat a temperature from about 30 to 150° C., preferably in a forced-airoven. Microwave ovens, vacuum ovens and infrared heaters may also beused if desired. Typical drying times range from about 1 minute to 24hours and preferably range from about 10 minutes to 10 hours. When atwo-step coating process is employed, it is preferred to dry the binderpolymer before application of the lubricious polymer.

Preferably in accordance with the present invention, the process isconducted with a substantial absence of a plasma treatment step such asdescribed in PCT patent application publication number WO 99/60920. Morepreferably, there is no plasma treatment in the processes of the presentinvention.

The lubricious coatings that result from the coating processes of thepresent invention typically have a thickness of from about 0.05 to 20microns, and preferably from about 0.1 to about 10 microns. When atwo-step coating process is employed, the resulting coating preferablycomprises an inner layer that is rich, i.e., greater than 50%, in thebinder polymer which contacts the surface of the substrate, and an outerlayer which is rich, i.e., greater than 50%, in the lubricious polymerwhich contacts the inner layer. The outer layer, which is rich in thelubricious polymer, has an outer surface that becomes lubricious whenexposed to an aqueous or organic liquid. When a one-step coating processis employed, the resulting coating comprises a single layer that ispreferably a substantially homogeneous mixture of the binder polymer andthe lubricious polymer. However, since the binder polymer will oftenhave more affinity for the substrate than the lubricious polymer, it isbelieved that there may be a higher concentration of the binder polymerwithin or near the surface of the substrate.

The particular manner in which the magnetic susceptible agents isincorporated into the coating is not critical to the present invention.In a preferred aspect of the invention, in order to incorporate themagnetic susceptible agents into the coating of the substrate, agadolinium complex is added into one or more of the liquid mediums inwhich the device is dipped. The liquid medium, e.g., third liquidmedium, is preferably an aqueous solution or dispersion containing awater-soluble or water-dispersible paramagnetic compound. The preferredaqueous solutions are those containing either an inorganic salt such assodium phosphate or a water-soluble polymer such as poly(N-vinylpyrrolidone), or both. The dipping step is preferably followed by dryingeither in air, an oven, or any other suitable heat-generation source.This coating process may be repeated as necessary until sufficientloading of the paramagnetic compound is deposited on the surfaces of themedical device. Alternatively, the paramagnetic compound may bedissolved or suspended in the coating solution and the paramagneticcompound is deposited on or impregnated in the polymeric matrix of themedical device. Furthermore, the paramagnetic compound may be depositedon or impregnated in the medical device by a separate coating step froman aqueous medium containing a water-miscible organic solvent.

In another aspect of the invention, the magnetic susceptible agents isimbibed into the surface of the medical device. In order to imbibe themagnetic susceptible agents into the medical device in accordance withthe processes of the present invention, a polymeric substrate having amatrix with (i) an internal region comprising a substrate polymer (asdescribed above) and (ii) an outer surface is contacted with a liquidmedium (as described above) having solvency for the substrate polymer.As used herein, the term “solvency” means that the liquid medium is asolvent for the substrate polymer (at the coating temperature) or iseffective to promote swelling of the substrate polymer. The contactingcan be conducted prior to, simultaneously with or after the applicationof the lubricious polymer to the polymeric substrate. Preferably, thecontacting with the liquid medium comprising the magnetic susceptibleagents is conducted prior to the application of the lubricious polymer.As used herein the term “imbibing” means to cause the transport of themagnetic susceptible agents from the liquid medium to the internalregion of the matrix of the substrate polymer. The liquid mediumcomprises an effective concentration of the magnetic susceptible agentsto promote the imbibing of the magnetic susceptible agents into thematrix of the substrate polymer.

The imbibing process is typically carried out at atmospheric pressure,and at a temperature of from about 20 to 90° C. by dipping, spraying,rolling or otherwise contacting the polymeric substrate in the liquidmedium for a relatively short duration such that there is preferably nomore than a 10% change, more preferably no more than a 7% change ineither the longitudinal or horizontal dimension or shape upon drying ofthe polymeric substrate. Preferably, the cross-sectional dimension,e.g., diameter of a catheter, evidences no more than a 10% change in thecross-sectional dimension after contacting with the liquid medium ascompared to the cross-sectional dimension prior to said contacting. Theresulting imbibed substrate can be dried as described above eitherbefore or after applying the lubricious coating.

In another aspect of the invention, the polymeric substrate and themagnetic susceptible agent are coextruded to form a molded element whichcomprises a portion or all of the medical device. After extrusion, themedical device can be coated with lubricious polymers as describedabove. Further details concerning the conditions for extrusion andapparatus for extrusion are known to those skilled in the art.

The loading of the paramagnetic compound in the lubricious coating isgoverned by the T₁ relaxation time of the water molecules in thecoating. In general, a sufficient loading, i.e., concentration, of theparamagnetic compound is required to reduce the T₁ relaxation time by atleast 10%, preferably 50% and more preferably 90% of the background suchthat a reasonably clear MRI can be obtained. The percent loading iscontrolled by the concentration of the paramagnetic compound in thesolution or dispersion, the length of dipping time, and the number ofcoats applied. These operating conditions can be readily chosen by thosewho are skilled in the art for a given substrate material, a givenparamagnetic compound and for a specific application. Further detailsconcerning the loading required for a particular situation can bedetermined by one skilled in the art.

EXAMPLES

The following examples are provided for illustrative purposes and arenot intended to limit the scope of the claims that follow.

In the following examples, in order to measure relaxation effects in themagnetic field, inversion-recovery experiments were conducted usingnuclear magnetic resonance (NMR). An inversion-recovery experiment is astandard method for determining the spin-lattice relaxation time T₁. Inthis experiment, the sample is pulsed 180° in the x direction. Theevolution of the magnetization vector is followed as magnetizationvector relaxes back to realignment with the applied magnetic field inthe z direction).

The equation to find T₁ is the following:M _(o) −M _(z) =A e ^(−t/T1)Mz is the magnetization in the z-direction at the time t; A is aconstant whose value depends on initial conditions.

The effect of super-paramagnetic particles on spin-spin relaxation timeis detected by measuring the line width of the observed NMR signals. Infact, since shortening either longitudinal or transverse relaxation timeresults in the broadening of the signal, this is a good screening toolto observe whether an agent will be visible in MR.

Example 1

This example illustrates the incorporation of a paramagnetic ion intothe coating of a medical device. The polymeric device used was a 7french guidewire that is constructed of a nylon/polyethylene copolymer.The guidewire was cut into nine inch samples, cleaned with isopropanol,and air-dried. The specimens were dipped into the bath containing P-106primer solution (a polyisocyanate available from Union CarbideCorporation of Danbury, Conn.) for 15 minutes. After dipping they wereplaced in a preheated forced air oven at 65° C. for 20 minutes.Thereafter, stents were removed from the oven and dipped in anothercoating bath containing POLYSLIP™ COATING T-503M (a dispersion ofpoly(acrylic acid) in a solvent mixture of dimethyl formamide, t-butylalcohol, and methyl ethyl ketone available from Union CarbideCorporation of Danbury, Conn.) for 10 seconds and followed by drying at65° C. for 2 hours. The coated stents were further dipped in an aqueoussodium phosphate bath that contained 10% diethylenetriamine-penta-aceticacid, gadolinium (III) dihydrogen salt hydrate for 10 minutes and driedat 65° C. for 11 hours. The finished coating was smooth and uniform.Three devices were treated. Both SEM and ESCA detected gadolinium on thesurface of each of the specimens (FIG. 1). Results from theinversion-recovery experiment were that all three samples reduced the T₁relaxation time of degassed water from 7 seconds to 0.3-0.7 seconds.Uncoated samples had no significant effect on the proton T₁ relaxationtime.

Example 2

This example illustrates the incorporation of a paramagnetic ion into apolymeric matrix. Kraton G, a styrene-butadiene copolymer (30 g) powderwas mixed with 49 g of Ferumoxsil Oral Suspension (MallinckrodtMedical). Ferumoxsil is a liquid formulation that includes iron oxidenanoparticles that is usually used for MR imaging of the GI tract. Theconcentration of iron in the formulation is 175 microgram/mL. Due to thepropensity of the iron oxide particles to settle, the Ferumoxsil wasmixed with an overhead mixer before addition to the polymer powder. Themixture was blended for 5 minutes in a Waring blender at the lowestspeed. The mixture was placed in a crystallization dish, covered with aKimwipe and dried in a vacuum oven at 110° C. overnight.

The resulting brown mixture (6 g) was placed in a stainless steel moldand mold was placed in a Greenard press. The platens were heated to 180°C. and the mixture was pressed for 2 minutes at this temperature. Plaquewas quench cooled by running ambient water through the press.

Samples of the plaque as well as a control plaque of Kraton G with noadditives were screened for effects in a magnetic field using NMR. Theplaque with Ferumoxsil showed a broader signal in the NMR relative tothe control plaque. The linewidth of the sample signal was 60 Hz and thelinewidth of the reference sample was 50 Hz. The effect on the magneticfield between the two samples was evident.

In addition, to further explore the super-paramagnetic effect,nanoparticles of iron oxide were extruded into polyethylene. Five (5) gof iron oxide (average 30 nm in size) particles were mixed with 20 g ofpolyethylene resin and extruded into polyethylene resin. The extrudedsample was analyzed by NMR and compared to that of neat extrudedpolyethylene resin. The spectra of the sample containing the iron oxidenanoparticles demonstrated a complex shape with the nominal line widthof approximately 276 Hz. Moreover, some components demonstrated evenmore pronounced broadenings, and the width at 10% of the height was 2kHz. The control sample increased the line width only slightly to 15 Hz.The signal of water itself under applied experimental conditions wasbroadened only to 8 Hz.

The extruded polyethylene sample containing the iron oxide nanoparticleswas coated using the procedure and materials described in Example 1, butomitting the gadolinium complex, and subsequently analyzed by NMR foreffect on the magnetic field. Quite surprisingly, the coating did notreduce the effect of the sample on the magnetic field. NMR resultsdemonstrated the line width at half height was 460 Hz and the width at10% of the height is 2.4 kHz.

Example 3

This example illustrates that different concentrations of theparamagnetic ion in dipping solution can be used to impart visibility inMR. The polymeric device used was a 7 french guidewire that isconstructed of a nylon/polyethylene copolymer. The guidewire was cutinto nine inch samples, cleaned with isopropanol, and air-dried. Thespecimens were dipped into a bath containing primer solution, P-106 for15 minutes. After dipping they were placed in a preheated forced airoven at 65° C. for 20 minutes. Thereafter, stents were removed from theoven and dipped in another coating bath containing POLYSLIP™ COATINGT-503M for 10 seconds and followed by drying at 65° C. for 2 hours. Thecoated stents were further dipped in an aqueous sodium phosphate baththat contained either 5 or 10% diethylenetriamine-penta-acetic acid,gadolinium (III) dihydrogen salt hydrate for 10 minutes and dried at 65°C. for 11 hours. The finished coating was smooth and uniform. NMRinvestigation indicated that both types of stents shortened the T₁relaxation time of water protons from 7 sec to 0.1 s and 0.4 s,respectively.

Example 4

This example illustrates that a sufficient concentration ofsuper-paramagnetic particles on the surface of a substrate results in adramatic perturbation of the magnetic field. This example illustratesthe incorporation of a paramagnetic ion into the coating of a medicaldevice. The polymeric device used was a 7 french guidewire that isconstructed of a nylon/polyethylene copolymer. The guidewire was cutinto nine inch samples, cleaned with isopropanol, and air-dried. Thespecimens were dipped into the primer solution, P-106, for 15 minutes.After dipping they were placed in a preheated forced air oven at 65° C.for 20 minutes. Thereafter, stents were removed from the oven and dippedin another coating bath containing POLYSLIP™ COATING T-503M for 10seconds and followed by drying at 65° C. for 2 hours. The coated stentswere dipped in the Ferumoxsil Oral Suspension for 10 minutes and thenair dried for 10 minutes. This last dipping step was repeated 6 times.

Example 5

This example illustrates the effect of an increase in the concentrationof iron oxide particles on the surface of a polymeric substrate.Standard T60 videotape made by 3M was wrapped around a 2 mm thick 5 cmlong plastic tube and analyzed as described above. The resultinglinewidth of the water protons was increased to 700 Hz relative to the40 Hz associated with the unwrapped tube. This result indicates thatdramatic effects to the applied magnetic field can be obtained ifsufficient of the super-paramagnetic particles can be immobilized on thesurface of a substrate. Coatings of super-paramagnetic particles can beobtained by dip-coating, powder coating, coextrusion and laminating. Thevideotape-wrapped tube is an illustration of the feasibility of thistechnology.

Example 6

This example illustrates that a paramagnetic compound can also beimbibed in a polymeric matrix of a medical device from an organicsolution. The water-soluble paramagnetic compound will migrate from thepolymeric matrix to the hydrated layer of the hydrophilic coating toproduce an image in magnetic resonance. Two pieces of 6 French(ethylene-vinyl acetate) copolymer stents are impregnated in a pyridinesolution containing 2.5% of the gadolinium-diethlenetriamine pentaaceticacid complex and 2% of distilled water for a period of 1 hour at roomtemperature. The stents are air-dried for 1 hour at room temperature.The stents are subsequently coated with a hydrophilic, lubriciouscoating using a procedure similar that in Example 1 with the exceptionthat there is no additional gadolinium complex added to the sodiumphosphate solution. The finished stents are covered uniformly with alayer of hydrophilic coating.

Similarly, in another experiment a 7 french guidewire constructed of anylon/polyethylene copolymer was incubated in a DMF/GdCl₃ solution andheated to 50° C. for 30 minutes. In this manner the imbibing of the Gd3+ion into the matrix of the stent was achieved (see FIG. 2). NMR analysisof these samples after coating with the procedure and materialsdescribed in Example 1 showed that samples formulated in this mannerreduced the T1 relaxation time of water from 3.5 seconds to 1.9 seconds.Moreover, the effect of the sample on the magnetic field of theinstrument was maintained for 4 hours.

Example 7

This example illustrates that the length of time that the coated devicehas contrast in the magnetic field can be controlled. Since thegadolinium complexes or salts are readily water-soluble there is atendency for them to diffuse out of the hydrophilic coating and into thesurrounding environment. In order to reduce the rate of the diffusioninto the surrounding environment a cellulose acetate coating was placedon the specimen (see FIG. 3). This was accomplished in the followingway. A 4% (w/v) cellulose acetate/acetone solution was prepared. Thegadolinium coated specimen (as prepared in Example 1) was dipped intothe cellulose acetate solution at ambient temperature. Especiallyeffective was a multiple dipping cycle with an air drying step inbetween each dip step. Samples prepared in this manner reduced therelaxation time of water from 3.7 seconds to below 1 second. Moreoverthis effect was maintained for approximately 100 minutes.

While the present invention has been described and exemplified with somespecificity, those skilled in the art will appreciate the variousmodifications, including variations, additions, and omissions, that maybe made in what has been described. For example, substances other thanthose specifically disclosed that can perturb the magnetic field canreplace the paramagnetic ion. Moreover, the magnetic susceptible agentscan be either incorporated into the hydrophilic lubricious coating byany of the suitable processes described above or by mixing within thepolymeric matrix of the medical device. For instance, if the medicaldevice is a catheter or stent the mixing may be achieved by using eitheran extruder or injection molding machine. Accordingly, it is intendedthat these modifications also be encompassed by the present inventionand that the scope of the present invention be limited solely by thebroadest interpretation that can lawfully be accorded the appendedclaims.

1. A process for making a lubricious medical device capable of being detected by magnetic resonance imaging, said process comprising: (a) contacting a surface of the device with (i) a binder polymer; and (ii) a hydrophilic polymer selected from the group consisting of poly(N-vinyl lactams), polysaccharides, polyacrylates, polyacrylamides, polyalkylene oxides, and copolymers and mixtures thereof; and (b) contacting the surface with an effective amount of a magnetic susceptible agent to cause the surface of the medical device to be detectable by magnetic resonance imaging and the process is conducted in the substantial absence of plasma treatment.
 2. The process of claim 1 wherein the surface is contacted with a first liquid medium comprising the binder polymer and subsequently contacted with a second liquid medium comprising the hydrophilic polymer.
 3. The process of claim 2 further comprising drying the surface prior to contacting with the second liquid medium.
 4. The process of claim 2 wherein the magnetic susceptible agent is comprised in at least one of the first liquid medium or the second liquid medium.
 5. The process of claim 2 further comprising contacting the surface with a third liquid medium comprising the magnetic susceptible agent.
 6. The process of claim 1 wherein the surface is contacted with a common liquid medium comprising the binder polymer and the hydrophilic polymer, and optionally the magnetic susceptible agent.
 7. The process of claim 6 further comprising drying the surface after contacting with the common liquid medium.
 8. The process of claim 1 wherein the magnetic susceptible agent is imbibed into the surface of the medical device.
 9. The process of claim 1 wherein the magnetic susceptible agent has a paramagnetic ion.
 10. The process of claim 9 wherein the magnetic susceptible agent has a paramagnetic ion selected from the group consisting of iron, manganese, chromium, cobalt, nickel and gadolinium.
 11. The process of claim 1 wherein the magnetic susceptible agent is an organometallic complex.
 12. The process of claim 11 wherein the magnetic susceptible agent is selected from the group consisting of diethylenetriamine-pentaacetic acid gadolinium (III) dihydrogen salt, tetrazacyclododecane tetraacetic acid gadolinium complex, tetrazazcyclotetradecane tetraacetic acid gadolinium complex, and mixtures thereof.
 13. The process of claim 1 wherein the magnetic susceptible agent is selected from the group consisting of super-paramagnetic particles and iodine containing contrast agents.
 14. The process of claim 1 wherein the substrate is selected from the group consisting of polyurethane, polyvinyl chloride, polyacrylate, polycarbonate, polystryrene, polyester resins, polybutadiene-styrene copolymers, nylon, polyethylene, polypropylene, polybutylene, silicon, polyvinyl acetate, polymethacrylate, polysulfone, polyisoprene, and copolymers thereof, glass, metal, ceramic and mixtures thereof.
 15. The process of claim 1 wherein the hydrophilic polymer is selected from the group consisting of polyN-vinylpyrrolidone, polyN-vinylpyrrolidone copolymers, carboxymethylcellulose, polyacrylic acid, cationically-modified hydroxyethylcellulose, polyethylene oxides, polyacrylamides and copolymers, and mixtures thereof.
 16. The process of claim 15 wherein the binder polymer comprises an isocyanate, aldehyde, epoxy, vinyl or carboxylic acid moiety.
 17. A process for making a lubricious medical device comprising a molded element capable of being detected by magnetic resonance imaging, said process comprising extruding a polymer in the presence of a magnetic susceptible agent to form the molded element; said molded element having a surface which is detectable by magnetic resonance imaging, and contacting a surface of the molded element with (i)a binder polymer; and (ii) a hydrophilic polymer selected from the group consisting of poly(vinyl lactams), polysaccharides, polyacrylates, polyacrylamides, polyalkylene oxides, and copolymers and mixtures thereof.
 18. A medical device capable of being detected by magnetic resonance imaging, said device comprising: (a) a polymeric substrate having a matrix with (i) an internal region comprising a substrate polymer; and (ii) an outer surface; and (b) a layer of a hydrophilic polymer affixed to the outer surface, said hydrophilic polymer being selected from the group consisting of poly(N-vinyl lactanis), polysaccharides, polyacrylates, polyacrylamides, polyallcylene oxides, and copolymers and mixtures thereof wherein the hydrophilic polymer comprises a magnetic susceptible agent detectable by magnetic resonance imaging. 